1. Field of the Invention
The present invention relates to a method of treating hyperglycemia, hyperlipidemia, and hepatic steatosis. Particularly, the present invention relates to a method of treating hyperglycemia, hyperlipidemia, and hepatic steatosis with antcin K isolated from Antrodia camphorata fruiting bodies.
2. The Prior Art
Diabetes mellitus hardly occurs in isolation but is most often a part of an array of metabolic abnormalities that includes insulin resistance, hyperinsulinemia, and hypertriglyceridemia. Type 2 diabetes is estimated to affect a population of about 300 million people by 2025, and it accounts for more than 90% of all diabetes mellitus. The pathogenesis of type 2 diabetes has been proposed as insulin resistance, which is attributed to insulin insensitivity in adipose tissue, skeletal muscle, or liver tissue and β-cell dysfunction.
The pancreas secretes insulin to maintain normal glucose homeostasis. The elevated glucose levels, after huge caloric intake, are rapidly returned to normal because secreted insulin stimulates glucose uptake via eliciting translocation of glucose transporter type 4 (GLUT4) from intracellular sites to the plasma membrane. Thus, GLUT4 has been regarded as a vital determinant of blood glucose homeostasis. For type 2 diabetic patients, levels of insulin-induced GLUT4 translocation in skeletal muscle of are markedly decreased. Therefore, enhancement of GLUT4 expression and translocation may be the target of drug development.
Glucose uptake from blood into peripheral tissues is promoted by two pathways, including insulin-dependent mechanisms leading to protein kinase B (PKB, also termed Akt) activation and contraction-regulated stimulation or hypoxia-regulated activation of 5′ adenosine monophosphate-activated protein kinase (AMPK). AMPK plays a dominant role in glucose and lipid metabolism. Since dysregulation of glucose and lipid metabolism is marked in type 2 diabetes, AMPK activators would be promising therapies.
Metformin is commonly used in the clinics as an antidiabetic drug in the management of type 2 diabetes, and it activates AMPK in both hepatocyte and skeletal muscle. However, it causes side effects of lactic acidosis, vomiting, diarrhea, nausea, vomiting, and flatulence.
Peroxisome proliferator-activated receptor α (PPARα) plays a key role in regulation of lipid metabolism and reduces circulating triglyceride (TG) concentrations via regulating numerous genes associated with lipogenesis and fatty acids oxidation. Fenofibrate, as one of PPARα agonists, has been used in the treatment of hypertriglyceridemia.
The high-fat diet-fed C57BL/6J mouse is a mouse model that is widely used to investigate disease mechanisms of type 2 diabetes and as a tool for developing novel therapeutic interventions, because the mouse could induce early type 2 diabetes, markedly increase adipose weights, produce insulin resistance, and increase blood glucose, total cholesterol (TC), and TG levels.
Antrodia camphorata (Polyporaceae, Aphyllophorales) is edible as a folk remedy in the treatment of a variety of diseases in Taiwan. It is rare and expensive because it grows only on the inner heartwood wall of the endemic evergreen Cinnamomum kanehirai. The mycelia, filtrate of broth, and fruiting bodies of A. camphorata exhibit numerous physiological functions. The fruiting bodies of A. camphorata contain terpenoids, such as antcins (A, B, and C), zhankuic acids (A, B, C, D, and E), 15α-acetyl-dehydrosulphurenic acid, dehydroeburicoic acid, dehydrosulphurenic acid, antcins E and F, methyl antcinate G, methyl antcinate H, and eburicoic acid. The solid culture of the fruiting bodies and the filtrate in submerged culture has been shown to have antioxidant activities.
Previous study had demonstrated that, in terms of in vivo metabolism, 13 terpenoids in A. camphorata were detected by using LC/MS/MS in rat plasma after oral administration, and plasma concentrations of ergostanoids were much higher than those of lanostanoids. The ergostanoids underwent reduction and hydroxylation reactions in vivo with their mean residence time (MRT) ranged from 3 to 6 hours. The lanostanoids were inactive to metabolic reactions and were slowly eliminated with an MRT of 9˜16 hours.
Antcin K (3α,4β,7β-trihydroxy-4α-methylergosta-8,24(28)-dien-11-on-25S-26-oic acid; abbreviated as AnK), an active triterpenoid from the fruiting bodies of basswood cultivated A. cinnamomea, is capable of inducing apoptotic cell death in human liver cancer Hep3B cells. Also, antcin K isolated from ethanol extracts of wild fruiting bodies of A. camphorata has shown concentration-dependent (1˜25 mM) anti-inflammatory effects (by modulation of leukocyte activity and inhibition of reactive oxygen species production) induced by chemotactic substances such as fMLP and TPA in human neutrophils.
Recent studies demonstrated that ergostatrien-3β-ol and dehydroeburicoic acid from A. camphorata exhibited excellent antihyperglycemic and antihyperlipidemic activities. Nevertheless, the effects of antcin K, the main constituent of the fruiting body of A. camphorata, on diabetes and dyslipidemia are still unknown.